Slow release properties and liver‐targeting characteristics of methotrexate erythrocyte carriers

Abstract

To study the releasing properties and tissue-targeting characteristics of methotrexate-loaded red blood cells (MTX-RBCs), pharmacokinetics and tissue distributions of intravenous injected MTX-RBCs and free MTX were compared. MTX-RBCs were made from rat erythrocytes using a hypertonic method. After i.v. injection of MTX-RBCs or free MTX to rats, both plasma and tissue homogenate samples at each time-point were collected and analyzed by RP-HPLC. From this data, pharmacokinetic parameters and tissue distributions of MTX were obtained. MTX-RBCs were successfully produced by the hypertonic method. After i.v. injection, MTX-RBCs displayed more than three times longer half-life and MRT than free MTX, and the velocity of MTX clearance from plasma was much slower. The ratio of area under the concentration time curve (AUC)(tissue) to AUC(plasma) in the liver was clearly higher than that for other organs after MTX-RBCs administration; MRT in the liver was also longer. This study has demonstrated that the hypertonic method for making MTX-RBCs has led to a preparation with slow release properties as well as liver-targeting characteristics in rats. This approach offers considerable potential for the treatment of tumors in liver, which would merit further investigation.

Preparation and in-vitro characterization of tramadol-loaded carrier erythrocytes for long-term intravenous delivery

“…We reached 95% entrapment efficiency for tramadol in our laboratory. This was remarkable compared with the results published for amphotericin B (15–18%), methotrexate (60%), prednisolone (85.4%) and, obviously, for large molecular weight drugs such as bovine serum albumin (59.8%), β ‐glucocerebrosidase (40–50%), and insulin (5%), upon loading in erythrocytes using the same method [13,48–52] …”

“…This was remarkable compared with the results published for amphotericin B (15-18%), methotrexate (60%), prednisolone (85.4%) and, obviously, for large molecular weight drugs such as bovine serum albumin (59.8%), b-glucocerebrosidase (40-50%), and insulin (5%), upon loading in erythrocytes using the same method. [13,[48][49][50][51][52] The use of glutaraldehyde in this study played a crucial role in improvement of drug loading parameters, from a nonsignificant final drug loading to almost complete drug retention within the cells. This effect could be clearly attributed to the well-established membrane stabilizing/cross-linking effect of glutaraldehyde, which in turn resulted in the decreased permeability of cell membrane to the drug during the final washing steps.…”

“…As an advantage, in the optimum conditions of the loading procedure (using more gentle methods for loading), the life‐span of the resulting carrier cells may be comparable with that of normal erythrocytes [1,6,7] . Erythrocytes have been used as circulating intravenous slow‐release carriers for the delivery of antineoplasm agents, antiparasitic drugs, antiretroviral agents, vitamins, steroids, antibiotics, and cardiovascular drugs among others [1,6–34] …”

Drug-loaded sickle cells programmed ex vivo for delayed hemolysis target hypoxic tumor microvessels and augment tumor drug delivery

“…For cisplatin specifically, the photo-oxidation rate of the drug-loaded SSRBCs may be slightly reduced by decreasing the PpIX concentration, the light energy dose (power and duration), and the temperature of the cells during photoactivation [22]. Efflux patterns for several other chemotherapeutic agents such as methotrexate [43], carboplatin [44], etoposide [45], fludarabine [46], bleomycin [47], and AraC [48] show 50% drug efflux ranging from minutes to several days after drug loading. For most of these drugs, the photo-oxidation conditions to produce delayed hemolysis release could be similar to those shown herein for calcein.…”

Vascular Drug Delivery Using Carrier Red Blood Cells: Focus on RBC Surface Loading and Pharmacokinetics

“…Ultimately, thorough understanding of pharmacokinetics, and the factors influencing it, permits the development of drugs with a higher probability of favorable safety and efficacy profiles. -fold increase in blood t 1/2 9-10.6 day RBC t 1/2 16-fold increase in blood t 1/2 2.4-4 day blood t 1/2 4-5-fold increase in duration of maximal asparagine lowering >10-fold increase in duration of total asparagine suppression Reduced ADA formation 44% increase in survival time vs. untreated [42,97,98] Maltose-Binding Protein Mouse Healthy~3-fold increase in blood t 1/2 [15] Methotrexate Mouse Healthy 3.5-fold increase in plasma t 1/2 2-fold increase in liver and spleen uptake [99] Phenylalanine Hydroxylase Mouse Naive Detectable drug in blood for at least 10 days post-injection vs. <6 h~5 0% reduction in blood Phe vs. 25% [100] Prednisolone Rat Healthy High drug uptake in liver [101] Polystyrene Nanoparticles Mouse Healthy 2-3-fold increase in blood exposurẽ 5-fold increase in lung uptake >50% decrease in spleen uptake No effect on RBC survival (t 1/2 = 33.5 h) [58]…”